How Do Drugs Enslave Our Brains?

Nora D. Volkow, M.D. Director National Institute on Drug Abuse @NIDAnews Natural & Drug Reinforcers Increase in NAc

1100 1000 AMPHETAMINE 900 800 frontal 700 600 cortex 500 400 300

% of Basal Release % of Basal 200 100 0 nucleus 0 1 2 3 4 5 hr Time After Amphetamine accumbens VTA/SN

200 FOOD

150

100 Drugs of abuse increase DA in the Empty Nucleus Accumbens, which is believed 50 Box Feeding 0 to trigger the neuroadaptions Release Basal of % 0 60 120 180 Time (min) that result in Di Chiara et al. Intravenous MPH (1 min) DA and the Rewarding 10 Effects of Drugs in Humans 8

) 6 10

- 4

0 High ( 2 TYROSINE TYROSINE 0 DOPA DOPA -2-10 0 10 20 30 40 DA DA DDAA Volkow et al., JPET 291:409-415, 1999. DA DA DA Oral MPH 10 () DA DA 8 DA D A DA methylphenidate raclopride D A D A

D A 10) 6 R D A R R D A D A R raclopride

R R - High (0 4 2 0 0 10 20 30 40 50 Change in DA (% change Bmax/Kd) DA increases induced by intravenous but not by oral administration of MPH were associated with the “high” … WHY? Pharmacokinetics of Oral and IV MPH in Baboon Brain

Oral (slow: NO “high”) 100

80 Drug reinforcing effects result from FAST DA increases emulating 60 iv (fast: intense “high”) phasic DA cell signaling (15-30 Hz), 40 which are implicated in reward and 20 conditioning rather than tonic DA

MP in Striatum in MP signaling (2-10 Hz), which are

(peak concentration) (peak 0 0 20 40 60 80 100 120 implicated in cognitive, motivational Time (min) and motoric systems. Volkow et al PNAS 2011. • D1R are predominantly stimulated by phasic DA and • D2R are stimulated by phasic and tonic DA. • Drug reward requires stimulation of D1R and is optimal when both D1R and D2R are stimulated Cocaine’s Rewarding Effects Entail Both Its Fast Stimulation of D1R & A Slower Stimulation of D2R

Luo Z et al., J Neurosci Sept 14, 2011 31(37):13180 –13190.

Smith RJ et al., Current Opinion in Neurobiology 2013, 23:546–552. Reward Circuit in Addiction

REWARD NAcc VP

TYROSINE TYROSINE

DOPA DOPA

DA DA DDAA DA DA DA “High” DA DA 10 DA DA DA methylphenidate raclopride DA DA 8

R DA DA raclopride )

R R DA R R DA R 6 10

- 4

Reports

0 - ( 2

Self 0 -2-10 0 10 20 30 40 Change in Dopamine Bmax/kd (Placebo - MP) Volkow et al., JPET 291(1):409-415, 1999. Methylphenidate-induced Increases in Striatal DA in Controls and in Detoxified Cocaine Abusers Placebo MP 10 P < 0.003 35 8 P < 0.001 30 25 6 20 15 21% 4 10 Normal Control 2 5 9% Report Self HIGH 0 % Bmax/Kd Change % 0 Controls Abusers Controls Abusers (n=20) (n = 20) Cocaine abusers showed decreased DA increases and reduced reinforcing Cocaine Abuser responses to MP Volkow et al., Nature 386:830-833, 1997. Reactivity of Dopamine System To Drug Consumption in Actively Using Addicted Subjects

Placebo MPH P < 0.001 P < 0.001 25

High 10 Kd / 20 8

Bmax 15

10) 6

- (1

10 report High

- 4 Self % Change 5 Cocaine abuser Low 2 14% 3% 0 Controls Abusers Controls Abusers (n=17) (n=17)

Active cocaine abusers showed a marked reduction in MPH-induced DA increases and Control subject in its reinforcing effects Volkow et al., Mol Psychiatry 2014 MP-Induced DA Change Controls vs Cocaine Abusers (with and without cues)

13%

P <0.001

Control subjects Psychiatry Psychiatry 2014

2 Mol

Cocaine abusers with CUE P <0.05 Volkow et al Volkow

P <0.05 Cocaine abusers with NEUTRAL MP increased DA in controls (p<0.001) whereas in cocaine abusers the effects were minimal and only significant in VS (p<0.05) Effects Of Chronic Cocaine In D1R and D2R Signaling During Intoxication D1R NAIVE D1R ACUTE

CHRONIC D1R/D2R

D2R

CHRONIC D2R D1R/D2R D1R CHRONIC D2R

ACUTE

Du et al J Neuroscience 2011 EXECUTIVE Motivation & Executive FUNCTION PFC Control Circuits ACG INHIBITORY OFC CONTROL SCC

Here we tested if, in addicted MOTIVATION/ subjects, changes in DA function DRIVE were linked with disruption of frontal activity as assessed by multiple tracer studies that evaluated in the same subject

dopamine D2 receptors and DA DA brain glucose metabolism (marker of brain function). DA DA D2 Receptors DA DA DA DA

signal

Metabolism Dopamine D2 Receptors are Lower in Addiction

Normal Controls 4.5 Cocaine Abusers 4

Cocaine 3.5

3 (Ratio (Ratio Index)

DA D2 Receptors D2 DA 2.5

2 Meth 1.5 15 20 25 30 35 40 45 50

3.2`

3

2.8 Alcohol 2.6 2.4

Bmax/Kd 2.2

2

1.8

1.6 Heroin 20 25 30 35 40 45 50 control addicted Volkow et al., Neuro Learn Mem 2002. D2R Overexpression in Sprague Dawleys

0 DA D2 Levels -20

60 p < 0.0005 -40 50 p < 0.0005 p < 0.01 40 p < 0.005 -60 30 p < 0.001 20 D2R Vector D2R -80 p < 0.10 10 p < 0.001

% ChangeD2R % -100 0 0 4 6 8 10 0 4 6 8 10 Time (days) Time (days) Thanos, PK et al., J Neurochem, 2001. D2R Overexpression In Alcohol Preferring Rats

Thanos et al., Alcohol Clin Exp Res. Over-expression of D2 receptors in rats markedly reduces alcohol intake Expected Consequences of Reduced Striatal D2R Signaling in Indirect Pathway

Glucose Metabolism FRONTAL CORTEX

 excitation

LOW D2 Receptors Thalamus

Striatum  inhibition ACC OFC 60 60

P < 0.01 P < 0.005 55 55

50 50 GPe /100g/min  inhibition 45

45 micromol/100g/min  inhibition micromol 40 40 VTA Controls Abusers Controls Abusers SN STN SNR-GPi Brain glucose metabolism is reduced in frontal cortex  excitation of cocaine abusers Volkow et al., PNAS 2011. Relationship Between Brain Glucose Metabolism and Striatal D2 Receptors

65

60

55

50

45

40 35 Control Cocaine Abuser 30 1. 2 2. 2. 2. 2. 3 3. 3. 98 2 4 6 8 2 4 0 8 0 OFC 7 0 6 0 5 0 4 Methamphetamine 0 3 Controls Abusers 02. 3 3. 3. 3. 3. 3. 3. 50 /100gr/min 389 1 2 3 4 5 6 50 4 36

Brain glucose metabolism glucose Brain 45

control addicted control 34 45 umol

40 32 30 40 35 28 0

Metabolism CG Metabolism OFC 26 35

(micromol/100g/min)

(micromol/100g/min) Metabolism Prefrontal (micromol/100g/min) 30 24 25 22 30 Controls Alcoholics 1.5 2 2.5 3 3.5 4 1.5 2 2.5 3 3.5 4 1.5 2 2.5 3 3.5 4 D2R VS D2R VS Volkow et al., PNASD2R 2011. VS D2 Receptors (BPND) DA D2 receptors (Bmax/Kd) (Bmax/Kd) (Bmax/Kd) DA D2 Receptors and Relationship to Brain Metabolism in Subjects with Family History for Alcoholism Volkow et al. Arch Gen Psychiatry 2006. 1.30 1.25 1.20 1.15

1.10 OFC 1.05 1.00

Relative metabolism Relative 0.950 0.900 4.0 4.2 4.4 4.6 4.8 5.0 1.05 1.00 0.95

CG 0.90 0.85

0.80 Relative metabolism Relative 0.75 4.0 4.2 4.4 4.6 4.8 5.0 Correlations between Metabolism and D2R P <0.005 D2R (Bmax/Kd) D2R were associated with metabolism in PREFRONTAL regions the disruption of which results in impulsivity and compulsivity Non-Addicted Brain Addicted Brain

PFC PFC (ACC, DLPFC (ACC, inferior PFC, BA44, lat lateral OFC) OFC)

Dorsal NAc NAc Dorsal Striatum Striatum Motor cortex STOP GO VTA VTA Motor Cortex

Amygdala Amygdala Hippocampus Hippocampus Controlled behavior Automatic behavior Volkow et al PNAS 2011 Striatal D2R (PET) and Brain Methylphenidate Decreases Reactivity (fMRI) to Drug & Impulsivity in Cocaine Abusers Food Cues in Cocaine Abusers (n=20) & Normalizes Cingulate Activity during Drug Stroop Test Methylphenidate > Placebo

dACC

OFC

Striatal D2R receptors correlated positively Correlation between activation in ventral with Cue reactivity in rvACC and OFC ACC and OFC and change in accuracy and negatively in dACC (MPH minus placebo) Tomasi et al., Human Brain Mapping, 2014. Goldstein & Volkow Neuropsychopharmacology, 2010. David Alexoff, Karen Apelskog, Helene Benveniste,Anat Biegon, Elisabeth Caparelli, Pauline Carter, Stephen Dewey,Congwu Du, Richard Ferrieri, Joanna Fowler, AndrewMike Gifford,Rich Rita Goldstein, Nils Hanik,Fritz hennm Jacob Hooker, Bud Jayne, Kun-eek Kil, Sunny Kim, Payton King, Nelly Klein,Hai-Dee Lee, Jean Logan, Jeming Ma,Martine Mirrione, Lisa Muench, Alicia Reid, Colleen Shea, Wynne Schiffer, Hanno Schieferstein, Matthias Schonberger, David Schlyer, Mike Schueller,Elena Shumay, Peter Thanos, Dardo Tomasi, Frank Telang, Paul Vaska, Nora Volkow, Gene-Jack Wang, Donald Warner, Chris Wong, Youwen Xu, Wei Zhu http://www.bnl.gov/CTN/: supported by DOE-OBER and NIH